Despite the success of modern chemotherapy in the treatment of certain types of leukemia and lymphoma and some other relatively rare cancers, few current anticancer therapies have met with significant clinical success in treatment of the most common forms of cancer. The poorly responsive cancers are typically solid tumors comprising both proliferating and non-proliferating cells. Typically, the anticancer drugs used today are effective predominantly against rapidly proliferating tumor cells, and are toxic to rapidly proliferating non-cancerous cells. Two general approaches are currently being pursued to overcome this problem. First, there is an intensive search for new drugs that are selective for cancer cells. A second strategy is that of targeting new or existing drugs specifically to tumors. Many attempts at applying this strategy have relied on monoclonal antibodies (Mabs) to carry a drug or toxin to the tumor. A major problem with this approach is tumor cell heterogeneity and the inability to deliver antibody conjugates to every tumor cell (Jain, 1989). One way of overcoming this problem is the use of enzyme-antibody conjugates which activate prodrugs to form diffusible cytotoxins (Bagshawe, 1989). This approach has been called antibody-directed enzyme prodrug therapy (ADEPT). The two-step ADEPT process requires the conjugation of a suitable enzyme to a monoclonal antibody which localizes the enzyme to the tumor. When most of the nonbound antibody-enzyme conjugate has been cleared, a prodrug is administered which can be activated by the enzyme to a cytotoxic species (Bagshawe, 1990). Though the ADEPT strategy is promising, it has a number of problems. First, the large majority of the Mab-enzyme conjugates do not localize in the tumor, and studies have shown that concentrations of the active drug in normal tissues can be greater than in the tumor (Antonio et al., 1990). Also, MAbs of high enough specificity are not available for many tumors. See, also Melton et al., 1996.
Other targeting approaches include the use of recombinant toxins, such as growth factors fused to a bacterial toxin (Fitzgerald et al., 1992), and the use of tumor-infiltrating lymphocytes genetically engineered to produce a protein such as tumor necrosis factor (TNF) (Rosenberg, 1992). No reports of improved activity of any of these targeting strategies has yet appeared.
In still another approach, a gene for the cancerostatic polypeptide Colicin E3 was introduced into an uncharacterized mixture of endogenous plasmids in C. oncolyticum (C. butyricum M-55, renamed because of its oncolytic activity; Schlechte, et al., 1988). This approach, however, was unsuccessful based on the inability to transform C. oncolyticum and the corresponding inability to show that the recombinants were expressing active protein. In addition, this approach is based on an anticancer agent that is a protein rather than a low molecular weight compound. At the present time, low molecular weight compounds constitute the majority of chemotherapeutic agents.
Human solid tumors, which make up more than 90% of all human cancers are known to comprise a hypoxic environment in that they are considerably less well oxygenated than normal tissues. Recent cancer treatment strategies focused on this aspect include the use of drugs that are toxic only under hypoxic conditions, e.g., tirapazamine, and gene therapy approaches based on the use of transcription factors that are inducible under hypoxic conditions, e.g., hypoxia-inducible factor 1 (HIF-1). See, e.g., Brown, 2000.
Despite advances in cancer treatment, significant side effects due to the toxicity of the chemotherapeutic agents in current use remains a problem. Gene therapy strategies have been attempted and are the subject of ongoing clinical trials. However, the lack of specificity of delivery systems and toxic side effects due to those delivery systems must be overcome in order for such strategies to have clinical relevance.
Accordingly, a need exists for selective targeting of toxic chemotherapeutic agents to solid tumor tissue without exposing healthy tissue to the agent.